Birnbaum
and Fenton review a wide array of experimental evidence from animals
showing that exposure to endocrine-disrupting compounds
in early development can cause cancer and/or increase sensitivity
to cancer-causing agents later in life.

Their
review then highlights how few human studies have been built upon
this understanding. Almost all human epidemiological research
into cancer risk from contaminant exposures examines chemical levels
only at the time of diagnosis or afterward. This approach
misses entirely the period of developmental sensitivity to exposures
that animal studies have identified [a recent
example being the Long Island
Breast Cancer study].

Birnbaum
and Fenton summarize this with two important questions about the
way most human studies have been conducted:

"Could
we be trying to correlate exposure and effect at the wrong
time? If it is prenatal, or early life stage, exposure that
is critical to disease susceptibility, why are we measuring
environmental chemicals in people once they have developed
breast cancer? The critical exposure window may have been
much earlier."

One
interesting pattern that emerges from their review of animal experiments
is that in utero exposure to several endocrine disrupting
compounds (including dioxin, atrazine and bisphenol A) can alter
mammary gland development in ways that prolong the period of sensitivity
to carcinogens. This suggests a different way of thinking
about the contribution of these contaminants to carcinogenesis:
even if they don't cause cancer directly, they contribute to cancer
risk by increasing vulnerability. No epidemiological study
has ever attempted to test for this sort of effect in people.

Birbaum
and Fenton begin their review with a very succinct summary of the
basic reasons why early developmental stages through puberty are
especially vulnerable to chemical exposure:

The
pace of and the nature of change in a developing fetus or child
is dramatically enhanced compared with that in an adult. An
embryo and fetus is changing quickly, with rapid cycles of cell
division and growth, and massive changes in the patterns of
gene activation over time. These cycles provide extensive opportunities
for mistakes to occur and be incorporated into the organism.
Sometimes these mistakes are mutagenic, sometimes they are based
on changes outside the genes. Comparable periods of cell division,
differentiation and growth are long since over in an adult.
Hence the chances for mistakes to be made and incorporated aren't
nearly as common in an adult compared to an embryo or fetus.

Second,
physiological barriers such as the blood-brain barrier are not
yet complete in the womb.

Finally,
the enzymatic mechanisms that work to detoxify contaminants
in adults are not fully developed until after birth.

They
then cite two examples offering "unequivocal evidence"
from human studies demonstrating that developmental exposures can
cause cancers in children and young adults. This comes from studies
from ionizing radiation and the synthetic estrogen diethylstilbestrol.

Studies
of a range of other human exposures suggest causal relationships
between developmental exposure and subsequent cancers, but the evidence,
while strong, is not as conclusive as for DES and radiation. These
other studies implicate occupational exposures of parents to brain
cancers in children, pesticides, paints, paint thinners and solvents
in causing leukemia, and cigarette smoke and childhood cancer, among
others. In this discussion Birnbaum and Fenton also comment on one
of the chief obstacles impeding epidemiological studies of childhood
cancers: they are so uncommon in the general population
that prospective studies rarely have a sufficient sample size to
find positive results.

Turning
to animal studies where experimental studies are possible, Birnbaum
and Fenton observe that "data from experimental animal studies
for developmental exposures and early lifestage or adult cancer
is far more extensive and convincing than the current epidemiological
data."

They
review an extensive literature showing conclusively that
prenatal and early postnatal exposure to various types of radiation
and to many different chemicals cause cancers later in life in the
exposed animals.

Induced
tumors span the gamut: skin carcinogenesis, liver ovarian, uterine
and pituitary tumors from prenatal x-ray exposure; respiratory tumors
from a wide array of mutagens, including ethyl-nitrosourea (ENU);
uterine tumors from ENU, dimethylbenz[a]anthracene (DMBA) and urethane;
nervous system tumors in a wide range of mammalian species from
ENU, etc.

In
careful, elegant experiments, scientists have also shown that developmental
exposure can heighten sensitivity to carcinogens later in life.
For example, studies of the industrial chemical, ethylene thiourea
(ETU), found that perinatal exposures alone did not affect cancer
risk. Individuals that had been exposed perinatally, however, developed
more cancers when exposed in adulthood than did others, also exposed
in adulthood, who had not been exposed perinatally (Chhabra
et al. 1992).

They
conclude this section of their review:

"Thus,
as seen from all the preceeding information, industrial chemicals,
drugs, and radiation have been associated with an elevated
incidence of neoplasms in both experimental animals and in
people following early life stage exposures. These studies
also suggest that fetal susceptibility (lack of metabolism,
protective barriers not formed, etc.), sensitive populations
(strain differences), and critical periods of target organ
development are key elements in the response to environmental
carcinogens."

Birnbaum
and Fenton then turn their focus specifically to endocrine-disrupting
compounds, beginning with a reminder that fetal exposure to one
endocrine disruptor, diethystilbestrol, is clearly linked to vaginal
cancer in young adult women and possibly linked to testicular cancer
in young adult men. Beyond those cases, there have been
almost no human epidemiological studies examining links between
developmental exposures and subsequent cancer risk.

Experimental
work with animals is more extensive, however, and as above with
exposures in general, it shows convincingly links between exposures
and cancer causation. The classic case here also is diethylstilbestrol,
but addresses many other compounds also.

For
example, when pregnant mice are injected with genistein (a phytoestrogen
abundant in soy), their female daughters develop mammary gland tumors.
Neonatal mice injected with very
low levels of genistein develop uterine cancer. Despite these
results and the popularity of soy formula, according to Birnbaum
and Fenton "there is a dramatic lack of epidemiologic
studies evaluating the effect of maternal (fetal) or infant soy
consumption and correlation with breast, uterine, or testicular
cancer."

Polyhalogenated
aromatic hydrocarbons
Birnbaum and Fenton provide an excellent short synopsis of experimental
work on the polyhalogenated aromatic hydrocarbons, that family of
brominated and/or chlorinated compounds that include the polychlorinated
biphenyls (PCBs), polybrominated biphenyls (PBBs) and dioxins. Animal
experiments establish definitive causal links between developmental
exposure to an array of these compounds and adverse effects later
in life, including cancers.

Specifically
with respect to dioxin, "there have been at least 18 published
animal cancer studies in rats, mice, hamsters, and fish demonstrating
cancer positive outcomes in both sexes and at multiple sites. Experimental
studies have also demonstrated that dioxins are potent tumor promoters,
enhancing both the incidence and multiplicity of tumors at multiple
sites following initiation with a direct acting mutagen."

Birnbaum
and Fenton acknowledge that evidence from animal experiments about
dioxin's link to mammary tumors is contradictory, but they point
to very recent human epidemiological
work indicating an association between developmental exposure
and heightened breast cancer risk. In general, the published animal
research on in utero exposure indicates that dioxin induces
changes in mammary gland development and structure that prolong
the developmental period of sensitivity to carcinogenesis. One interesting
set of animal experiments involved prenatal exposure to dioxin followed
by exposure to DMBA at sexual maturity. This more than doubled the
number of mammary tumors. Another suggests effects on maternal pituitary
weight and prolactin levels consistent with elevated estrogen levels.

Atrazine
and Bisphenol A
Recent studies of these two compounds show that in utero exposure
can prolong the period of sensitivity to carcinogens. Atrazine also
clearly alters the pattern of mammary gland development around puberty.

Birnbaum
and Fenton's concluding paragraph, below, should be read by all
epidemiologists contemplating work on endocrine disruption and carcinogenesis,
as well as by policy advocates, reporters and editorial writers.
It effectively rebukes any claims (e.g., in
the New York Times) that existing studies on the links between
EDCs and cancer risk exonerate the contaminants.

Human
Impact?
All of these studies have demonstrated that prenatal exposure
to EDCs can alter the hormonal mileau, reproductive tissue
development, and susceptibility to potential carcinogen exposure
in the adult. These compounds are not genotoxic, yet can have
significant adverse health outcomes. We must ask the questions:
Are the appropriate, sensitive animal strains being utilized
to test for endocrinologically-based diseases, such as breast
cancer? Are many of the adult rodents whose brain and endocrine
function are fully developed relatively insensitive when exposed
to EDCs as adults? There have been epidemiological studies
investigating the association of environmental chemicals,
including both organochlorines, such as PCBs and atrazine,
with breast cancer incidence (Sasco 2001). These particular
studies have measured the levels of exposure of these chemicals
in adult women who develop breast cancer. Could we be trying
to correlate exposure and effect at the wrong time? If it
is prenatal, or early life stage, exposure that is critical
to disease susceptibility, why are we measuring environmental
chemicals in people once they have developed breast cancer?
The critical exposure window may have been much earlier.